Project 3 of the CREATE Pharmacogenetics Research Network will characterize polymorphisms in members of the pathways regulating drug activity in Caucasians, Hispanic, Asian, and African American populations. This project stems from the clear evidence in quantitative and qualitative differences in clinically relevant polymorphisms between ethnic groups. As both Washington University and University of Southern California serve diverse patient population, the influence of ethnicity of variant frequency is of direct relevance to these centers. The specific aims of this project are: 1) Characterize genotype and allele frequency of drug pathway variants in Caucasian, Hispanic, Asian and African American populations 2) Confirm that the variants of interest are an inherited genotype 3) Describe gene flow for variants within the drug pathways This will be accomplished by analysis of genotype in 300 individuals from each of the four ethnic groups. Assessment of DNA from CEPH Reference Families will be used to confirm that the variant of interest is an inherited genotype. Population genetics models will also be used to define whether the pathway variants have been acquired in a systematic fashion or whether each gene has recombination as an isolated, unrelated event to the other genes in the pathway. Together these approaches will provide useful data on the variants of interest and important information of potential predictive impact for using pharmacogenetics to optimize therapy in all populations.